The main goal of this project is to understand the role of the B cell surface protein CD72 in the regulation of B cell development and responsiveness. These studies will make extensive use of CD72-deficient mutant mice, which have hyperresponsive B cells and defects in B cell development and selection. The first aim is to further define the mechanisms by which CD72 regulates responsiveness and development by examination of functional interactions between CD72 and other surface proteins and signaling molecules. These studies will take advantage of a number of other mutant mouse strains lacking proteins (e.g., CD 19, CD22, Lyn) that appear to have similar or opposing functions to those of CD72 and that may interact directly or indirectly with CD72 signaling. CD72 signaling will be examined in such mutant mice. The effects of CD72 deficiency upon signaling involving these other regulatory proteins will also be assessed. Mice doubly deficient for CD72 and these other proteins will be generated and their phenotype examined to further elucidate the interactions between CD72 and other negative or positive regulators of B cell responsiveness. The second aim is to define the role of specific motifs in the CD72 cytoplasmic tail in regulating B cell maturation and responsiveness. This will be done by generation of mice expressing CD72 in which particular amino acids thought to be involved in signaling have been mutated. The resultant mice will be characterized to see which of the defects present in CD72-deficient mice are still present or are restored to normal in these new mutants. The third aim is to study the mechanism(s) by which lack of CD72 alters tolerance using CD72-deficient mice that are transgenic for a specific B cell receptor (BCR) and either express or do not express the specific antigen recognized by that BCR. The final aim is to determine how interactions between CD72 and the semaphorin protein CD 100 regulate B cell responsiveness and development using mouse model systems overexpressing or lacking each of these proteins. These studies will be important for understanding the mechanisms regulating B cell development, tolerance and autoimmunity.